MMSL 2015, 84(3):94-103 | DOI: 10.31482/mmsl.2015.011

ACID DISSOCIATION CONSTANTS AND MOLECULAR DESCRIPTORS OF SOME XYLENE LINKED BISPYRIDINIUM OXIMESOriginal article

Namrata Singh1,2*, Ondøej Soukup ORCID...2,3, Rafael Doležal ORCID...1,2, Zdenėk Fišar1, Bhanushree Gupta4,5, Kallol K. Ghosh4, Kamil Kuča ORCID...2,3
1 Department of Psychiatry, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, KeKarlovu 11, 120 00 Prague 2, Czech Republic
2 Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic
3 Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defense, Trebesska 1575, Kralove, Czech Republic
4 School of Studies in Chemistry, Pt. Ravishankar Shukla University, Raipur (C.G.), 492010, India
5 Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur (U.P.), 208016 India

The present article is aimed at determination of acid dissociation constants (pKa), lipophilicity (logP) and hydrogen bond acceptor (HBA) and donor (HBD) counts of some novel xylene-linked bispyridiniumoxime based AChE reactivators. The choice was supported by their use in the therapy of acute intoxication with organophosphorus AChE inhibitors. UV-Vis spectrophotometry has been used to measure experimental pKa values at 27°C, while software Marvin Sketch (chemaxon) has been used to estimate structure based computational pKa, logP values and hydrogen bonding parameters. The results were compared with standard oximes (HI-6 and obidoxime) under similar conditions. All the calculated pKa values lie in the range of 7.45-9.85 which is well in agreement with most of the oxime reactivators studied so far.

Keywords: Oxime reactivators; acid dissociation constants; lipophilicity; hydrogen bonding; blood brain barrier

Received: April 28, 2015; Revised: June 3, 2015; Published: September 4, 2015  Show citation

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Singh, N., Soukup, O., Doležal, R., Fišar, Z., Gupta, B., Ghosh, K.K., & Kuča, K. (2015). ACID DISSOCIATION CONSTANTS AND MOLECULAR DESCRIPTORS OF SOME XYLENE LINKED BISPYRIDINIUM OXIMES. MMSL, 84(3), 94-103. doi: 10.31482/mmsl.2015.011
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    References

    1. Bhattacharjee, A. K.; Marek, E.; Le, H.T.; Gordon, R. K. Discovery of non-oxime reactivators using an in silico pharmacophore model of oxime reactivators of OP-inhibited acetylcholinesterase. Eur. J. Med. Chem. 2012, 49, 229-238 Go to original source... Go to PubMed...
    2. Bhattacharjee, A. K.; Kuca, K.; Musilek, K.; Gordon, R. K. In silico pharmacophore model for tabun-inhibited acetylcholinesterase reactivators: a study of their stereo electronic properties. Chem. Res.Toxicol. 2010, 23, 26-36. Go to original source... Go to PubMed...
    3. Sharma, R.; Gupta, B.; Singh, N.; Acharya, J. R.; Musilek, K.; Kuca, K.; Ghosh, K. K. Development and structural modifications of cholinesterase reactivators against chemical warfare agents in last decade: a review. Mini-Rev. Med. Chem. 2014, (PMID:25441834)
    4. Singh, N.; Ghosh, K. K.; Marek, J.; Kuca, K. Hydrolysis of carboxylate and phosphate esters using monopyridinium oximes in cationic micellar media. Int. J. Chem.Kinet. 2011, 43, 569-578 Go to original source...
    5. Gupta, B.; Singh, N.; Sharma, R.; Foretiæ, B.; Musilek, K.; Kuca, K.; Acharya, J. R.; Satnami, M. L.; Ghosh, K. K. Assessment of antidotal efficacy of cholinesterase reactivators against paraoxon: In vitro reactivation kinetics and physicochemical properties. Bioorg. Med. Chem. Lett. 2014, 24, 4743-4748 Go to original source... Go to PubMed...
    6. Voicu, V. A.; Bajgar, J.; Medvedovici, A.; Radulescu F. S.; Miron D. S. Pharmacokinetics and pharmacodynamics of some oximes and associated therapeutic consequences: a critical review. J. Appl. Toxicol. 2010, 30, 719-729 Go to original source... Go to PubMed...
    7. Voicu, V. A.; Sârbu, C.; Tache, F.; Micãle, F.; Rãdulescu, Ē. F.;Sakurada, K.; Ohta, H.; Medvedovici, A. Lipophilicity indices derived from the liquid chromatographic behavior observed under bimodal retention conditions (reversed phase/hydrophilicinteraction): Application to a representative set of pyridinium oximes. Talanta. 2014,122, 172-179 Go to original source... Go to PubMed...
    8. Singh, N.; Ghosh, K. K.; Marek, J.; Kuca, K. Effect of some pyridinium based compounds on hydrolysis of carboxylate ester, Indian J. Chem. 2012, 51, 611-616
    9. Gupta, B.; Sharma, R.; Singh, N.; Karpichev, Y.; Satnami, M. L.; Ghosh, K. K. Reactivity studies of carbon, phosphorus and sulfur-based acyl sites with tertiary oximes in gemini surfactants. J. Phys. Org. Chem. 2013, 26, 632-642 Go to original source...
    10. Esposito, E. X.; Stouch, T. R.; Wymore, T.; Madura, J. D. Exploring the physicochemical properties of oxime-reactivation therapeutics for cyclosarin, sarin, tabun, and VX inactivated acetylcholinesterase. Chem. Res. Toxicol. 2014, 27, 99-110 Go to original source... Go to PubMed...
    11. Voicu, V.; Sora, I.; Sârbu, C.; David, V.; Medvedovici, A. Hydrobhobicity/ hydrophilicity descriptors obtained from extrapolated chromatographic retention data as modelling tools for biological distribution: application to some oxime type acetylcholinesterase reactivators. J. Pharm. Biomed. Anal. 2010, 52, 508-516 Go to original source... Go to PubMed...
    12. Voicu, V.; Medvedovici, A.; Rãdulescu, M.; Iorgulescu, E. E.; David, V. Unusual retention behavior of some cationic-type aldoximes used as AchE reactivators under ion-pairing liquid chromatographic mechanism. Anal. Lett. 2010, 43, 1267-1276 Go to original source...
    13. Lorke, D. E.; Kalasz, H.; Petroianu G.A.; Tekes K. Entry of oximes into the brain: a review. Curr. Med. Chem. 2008, 15, 743-753 Go to original source... Go to PubMed...
    14. Musilek, K.; Kuca, K.; Jun, D.; Dohnal, V.; Dolezal M. Synthesis of a novel series of non-symmetrical bispyridinium compounds bearing a xylene linker and evaluation of their reactivation activity against tabun and paraoxon-inhibited acetylcholinesterase, J. Enzym. Inhib. Med. Chem. 2007, 22, 425-432 Go to original source... Go to PubMed...
    15. Musilek, K.; Holas, O.; Misik, J.; Pohanka, M.; Novotny, L.; Dohnal, V.; Opletalove, V.; Kuca, K. Monooxime-monocarbamoylbispyridinium xylene-linked reactivators of acetylcholinesterase-synthesis, in vitro and toxicity evaluation, and docking studies, Chem. Med. Chem. 2010, 5, 247-254
    16. Acharya, J.; Gupta, A. K.; Mazumder, A.; Dubey, D. K. In vitro reactivation of sarin inhibited electric eel acetylcholinesterase by bis-pyridinium oximes bearing methoxy ether linkages, Toxicol. in Vitro, 2008, 22, 525-530 Go to original source... Go to PubMed...
    17. Acharya, J.; Gupta, A. K.; Dubey, D. K.; Raza, S. K. Synthesis and evaluation of novel bis-pyridinium oximes as reactivators of DFP-inhibited acetylcholinesterase, Euro. J. Med. Chem. 2009, 44, 1335-1340 Go to original source... Go to PubMed...
    18. Acharya, J.; Gupta, A. K.; Mazumder, A.; Dubey, D. K. In-vitro regeneration of sarin inhibited electric eel acetylcholinesterase by bis-pyridinium oximes bearing xylene linker, Euro. J. Med. Chem. 2009, 44, 1326-1330 Go to original source... Go to PubMed...
    19. Acharya, J.; Rana, H.; Kaushik, M.P. Synthesis and in vitro evaluation of xylene linked carbamoyl bis-pyridiniummonooximes as reactivators of organophosphorus (OP) inhibited electric eel acetylcholinesterase (AChE). Eur. J. Med. Chem. 2011, 46 3926-3933 Go to original source... Go to PubMed...
    20. Gray, A. P. Design and structure-activity relationships of antidotes to organophosphorus anticholinesterase agents, Drug Metab. Rev. 1984, 15, 557-589. Go to original source... Go to PubMed...
    21. Tougu, V. Acetylcholinesterase: Mechanism of Catalysis and Inhibition, Curr. Med. Chem.: Cent. Nerv. Syst. Agents. 2001, 1, 155-170. Go to original source...
    22. Albert, A.; Sergeant, E. P. Determinations of Ionization Constants, a Laboratory Manual; Chapman and Hall Press: London, 1971.
    23. Acharya, J.; DubeyD. K., Srivastava, A. K.; Raza, S. K. In vitro reactivation of sarin-inhibited human acetylcholinesterase (AChE) by bis-pyridinium oximes connected by xylene linkers. Toxicol. in Vitro. 2011, 25, 251-256. Go to original source... Go to PubMed...
    24. Wiczling, P.; Kawczak, P.; Nasal, A.; Kaliszan, R. Simultaneous determination of pKa and lipophilicity by gradient RP HPLC. Anal. Chem. 2006, 78, 239-249. Go to original source... Go to PubMed...
    25. Lombardo, F.; Shalaeva, M. Y.; Tupper, K. A.; Gao, F.; Abraham, M. H. A tool for lipophilicity determination in drug discovery, J. Med. Chem. 2000, 43, 2922-2928. Go to original source... Go to PubMed...
    26. Lipinski, C.A.; Lombardo, F.; Dominy, S.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery. Adv. Drug Deliv. Rev. 1997, 23, 3-25. Go to original source...
    27. Walters, W.P. Going further than Lipinski's rule in drug design. Expert Opin. Drug Discov. 2012, 7, 99-107. Go to original source... Go to PubMed...
    28. Bhal, S. K.; Kassam, K.; Peirson, I. G.; Pearl, G. M. The Rule of Five Revisited: Applying Log D in Place of Log P in Drug-Likeness Filters, Mol. Pharmaceutics, 2007, 4, 556-560. Go to original source... Go to PubMed...
    29. Sethi, B.; Soni, M.; Kumar, S.;Gupta, G.D.; Mishra, S.; Singh, R. Lipophilicity measurement through newer techniques. J. Pharm. Res. 2010, 3, 345-351.
    30. Goodwin, J. T.; Conradi, R. A.; Ho, N. F.; Burton, P. S. Physicochemical Determinants of Passive Membrane Permeability: Role of Solute Hydrogen-Bonding Potential and Volume, J. Med. Chem. 2001, 44, 3721-3729. Go to original source... Go to PubMed...
    31. Clark, D. E. Chapter 10. Computational Prediction of ADMET Properties: Recent Developments and Future Challenges. Annu. Rep. Comput. Chem. 2005, 1, 133. Go to original source...
    32. Karasova, J. Z.; Pohanka, M.; Musilek, K.; Zemek, F.; Kuca, K. Passive diffusion of acetylcholinesterase oxime reactivators through the blood-brain barrier: Influence of molecular structure. Toxicol. in Vitro, 2010, 24, 1838. Go to original source... Go to PubMed...
    33. Gupta, B.; Sharma, R.; Singh, N.; Kuca, K.; Acharya, J. R.; Ghosh, K. K. In vitro reactivation kinetics of paraoxon- and DFP-inhibited electric eel AChE using mono- and bis-pyridinium oximes.Arch. Toxicol. 2014, 88, 381-390. Go to original source... Go to PubMed...
    34. Petroianu, G. A.; Lorke, D. E.; Athauda, G.; Darvas, F.; Kalasz, H. Pralidoxime and Obidoxime: Phosphylation induced Changes in logP (partition coefficient). J. Environ. Immunol. Toxicol. 2014, 1, 35-40. Go to original source...
    35. Tetko, I. V.; Tanchuk, V. Y.; Kasheva, T. N.; Villa, A-E. P. Internet Software for the Calculation of the Lipophilicity and Aqueous Solubility of Chemical Compounds. J. Chem. Inf. Comput. Sci. 2001, 41, 246-252. Go to original source... Go to PubMed...
    36. Eros, D.; Kövesdi, I.; Orfi, L.; T-Novák, K.; Acsády, G.; Kéri, G. Reliability of logP predictions based on calculated molecular descriptors: a critical review. Curr Med Chem. 2002, 9, 1819-1829. Go to original source... Go to PubMed...
    37. Liao, C.; Nicklaus, M. C. Comparison of Nine Programs Predicting pKa Values of Pharmaceutical Substances, J. Chem. Inf. Model. 2009, 49, 2801-2802. Go to original source... Go to PubMed...
    38. Reijenga, J.; Hoof, A. V.; Loon, A. V.; Teunissen, B. Development of Methods for the Determination of pKa Values, Anal. Chem. Insights, 2013, 8, 53-71. Go to original source... Go to PubMed...
    39. Schüürmann, G.; Cossi, M.; Barone, V.; Tomasi, J. Predication of the pKa of carboxylic acids using the ab initio continuum-solvation model PCM-UAHF. J. Phys. Chem. A. 1998, 102, 6706-6712. Go to original source...

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